Abstract
Metastatic invasion of tumors into peripheral tissues is known to rely upon protease-mediated degradation of the surrounding stroma. This remodeling process uses complex, actin-based, specializations of the plasma membrane termed invadopodia that act both to sequester and release matrix metalloproteinases. Here we report that cells of mesenchymal origin, including tumor-associated fibroblasts, degrade substantial amounts of surrounding matrix by a mechanism independent of conventional invadopodia. These degradative sites lack the punctate shape of conventional invadopodia to spread along the cell base and are reticular and/or fibrous in character. In marked contrast to invadopodia, this degradation does not require the action of Src kinase, Cdc42 or Dyn2. Rather, inhibition of Dyn2 causes a marked upregulation of stromal matrix degradation. Further, expression and activity of matrix metalloproteinases are differentially regulated between tumor cells and stromal fibroblasts. This matrix remodeling by fibroblasts increases the invasive capacity of tumor cells, thereby illustrating how the tumor microenvironment can contribute to metastasis. These findings provide evidence for a novel matrix remodeling process conducted by stromal fibroblasts that is substantially more effective than conventional invadopodia, distinct in structural organization and regulated by disparate molecular mechanisms.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1099-1110 |
| Number of pages | 12 |
| Journal | Oncogene |
| Volume | 35 |
| Issue number | 9 |
| DOIs | |
| State | Published - Mar 3 2016 |
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ASJC Scopus subject areas
- Molecular Biology
- Cancer Research
- Genetics
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Stromal fibroblasts facilitate cancer cell invasion by a novel invadopodia-independent matrix degradation process. / Cao, H.; Eppinga, R. D.; Razidlo, Gina; Krueger, E. W.; Chen, J.; Qiang, L.; Mc Niven, Mark A.
In: Oncogene, Vol. 35, No. 9, 03.03.2016, p. 1099-1110.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Stromal fibroblasts facilitate cancer cell invasion by a novel invadopodia-independent matrix degradation process
AU - Cao, H.
AU - Eppinga, R. D.
AU - Razidlo, Gina
AU - Krueger, E. W.
AU - Chen, J.
AU - Qiang, L.
AU - Mc Niven, Mark A
PY - 2016/3/3
Y1 - 2016/3/3
N2 - Metastatic invasion of tumors into peripheral tissues is known to rely upon protease-mediated degradation of the surrounding stroma. This remodeling process uses complex, actin-based, specializations of the plasma membrane termed invadopodia that act both to sequester and release matrix metalloproteinases. Here we report that cells of mesenchymal origin, including tumor-associated fibroblasts, degrade substantial amounts of surrounding matrix by a mechanism independent of conventional invadopodia. These degradative sites lack the punctate shape of conventional invadopodia to spread along the cell base and are reticular and/or fibrous in character. In marked contrast to invadopodia, this degradation does not require the action of Src kinase, Cdc42 or Dyn2. Rather, inhibition of Dyn2 causes a marked upregulation of stromal matrix degradation. Further, expression and activity of matrix metalloproteinases are differentially regulated between tumor cells and stromal fibroblasts. This matrix remodeling by fibroblasts increases the invasive capacity of tumor cells, thereby illustrating how the tumor microenvironment can contribute to metastasis. These findings provide evidence for a novel matrix remodeling process conducted by stromal fibroblasts that is substantially more effective than conventional invadopodia, distinct in structural organization and regulated by disparate molecular mechanisms.
AB - Metastatic invasion of tumors into peripheral tissues is known to rely upon protease-mediated degradation of the surrounding stroma. This remodeling process uses complex, actin-based, specializations of the plasma membrane termed invadopodia that act both to sequester and release matrix metalloproteinases. Here we report that cells of mesenchymal origin, including tumor-associated fibroblasts, degrade substantial amounts of surrounding matrix by a mechanism independent of conventional invadopodia. These degradative sites lack the punctate shape of conventional invadopodia to spread along the cell base and are reticular and/or fibrous in character. In marked contrast to invadopodia, this degradation does not require the action of Src kinase, Cdc42 or Dyn2. Rather, inhibition of Dyn2 causes a marked upregulation of stromal matrix degradation. Further, expression and activity of matrix metalloproteinases are differentially regulated between tumor cells and stromal fibroblasts. This matrix remodeling by fibroblasts increases the invasive capacity of tumor cells, thereby illustrating how the tumor microenvironment can contribute to metastasis. These findings provide evidence for a novel matrix remodeling process conducted by stromal fibroblasts that is substantially more effective than conventional invadopodia, distinct in structural organization and regulated by disparate molecular mechanisms.
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UR - http://www.scopus.com/inward/citedby.url?scp=84959544725&partnerID=8YFLogxK
U2 - 10.1038/onc.2015.163
DO - 10.1038/onc.2015.163
M3 - Article
C2 - 25982272
AN - SCOPUS:84959544725
VL - 35
SP - 1099
EP - 1110
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 9
ER -